title: p38 mitogen-activated protein kinase-dependent transactivation of ErbB receptor family: a novel common mechanism for stress-induced IRS-1 serine phosphorylation and insulin resistance.
abstract: OBJECTIVE
  Stress stimuli such as tumor necrosis factor (TNF) have been shown to induce insulin receptor substrate (IRS)-1 serine phosphorylation and insulin resistance by transactivation of ErbB receptors. We aimed at elucidating the potential role of p38 mitogen-activated protein kinase (p38MAPK) in mediating stress-induced ErbB receptors activation.
  
  
  METHODS
  p38MAPK effect on ErbBs transactivation and insulin signaling was assessed in Fao or HepG2 cells, exposed to stress stimuli, and on metabolic parameters in ob/ob and C57/BL6 mice.
  
  
  RESULTS
  High-fat diet-fed mice and ob/ob mice exhibited elevated hepatic p38MAPK activation associated with glucose intolerance and hyperinsulinemia. Liver expression of dominant-negative (DN)-p38MAPKα in ob/ob mice reduced fasting insulin levels and improved glucose tolerance, whereas C57/BL6 mice overexpressing wild-type p38MAPKα exhibited enhanced IRS-1 serine phosphorylation and reduced insulin-stimulated IRS-1 tyrosine phosphorylation. Fao or HepG2 cells exposed to TNF, anisomycin, or sphingomyelinase demonstrated rapid transactivation of ErbB receptors leading to PI3-kinase/Akt activation and IRS-1 serine phosphorylation. p38MAPK inhibition either by SB203580, by small interfering RNA, or by DN-p38MAPKα decreased ErbB receptors transactivation and IRS-1 serine phosphorylation and partially restored insulin-stimulated IRS-1 tyrosine phosphorylation. When cells were incubated with specific ErbB receptors antagonists or in cells lacking ErbB receptors, anisomycin- and TNF-induced IRS-1 serine phosphorylation was attenuated, despite intact p38MAPK activation. The stress-induced p38MAPK activation leading to ErbB receptors transactivation was associated with intracellular reactive oxygen species generation and was attenuated by treatment with antioxidants.
  
  
  CONCLUSIONS
  Hepatic p38MAPK is activated following various stress stimuli. This event is upstream to ErbB receptors transactivation and plays an important role in stress-induced IRS-1 serine phosphorylation and insulin resistance.
authors.affiliation: Institute of Endocrinology, Chaim Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Rina
authors.initials: R
authors.lastname: Hemi
authors.forename: Yafit
authors.initials: Y
authors.lastname: Yochananov
authors.forename: Ehud
authors.initials: E
authors.lastname: Barhod
authors.forename: Michal
authors.initials: M
authors.lastname: Kasher-Meron
authors.forename: Avraham
authors.initials: A
authors.lastname: Karasik
authors.forename: Amir
authors.initials: A
authors.lastname: Tirosh
authors.forename: Hannah
authors.initials: H
authors.lastname: Kanety
mesh_terms: D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D047468:Immunoprecipitation; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000841:Anisomycin; D004791:Enzyme Inhibitors; D007093:Imidazoles; D055504:Insulin Receptor Substrate Proteins; D011725:Pyridines; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D012694:Serine; D013108:Sphingomyelin Phosphodiesterase; D048069:Tumor Necrosis Factors; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580